Modeling myeloid malignancies with patient-derived iPSCs

Abstract

Modeling human diseases with patient-derived induced pluripotent stem cells (iPSCs) offers unique research opportunities and is particularly attractive for hematology research. Whereas monogenic inherited blood diseases featured prominently among the first proof-of-principle studies of iPSC modeling, malignant hematologic disorders have been off to a slower start. This has been due to challenges in the derivation of iPSCs from cancer cells and the need to establish robust differentiation protocols and to standardize phenotypic assays of iPSC-derived hematopoiesis. Recent studies of iPSC modeling of myeloid malignancies exploited the clonal heterogeneity of patient samples to derive genetically matched normal controls and recapitulate the clonal evolution of the disease. Comparisons of the malignant phenotypes and molecular signatures of primary leukemic cells, derived iPSCs, and their hematopoietic progeny stress the importance of the cell-of-origin in oncogenesis and enable investigation of the interplay between cell identity and the cancer genome. Larger collections of genetically diverse iPSC lines and more readily scalable hematopoietic differentiation protocols, ideally mimicking adult bone marrow-derived hematopoiesis, would further empower applications of iPSC modeling in myeloid malignancy in the future. Nevertheless, with recent progress in this field, the stage is set for the wider adoption of this model system by the hematology community.